The present invention relates to a preservative for emulsion, said preservative containing sorbic acid or a pharmaceutically acceptable salt thereof and exhibiting superior preservation effect at a low concentration, and to an emulsion containing said compound or a preservative for emulsion containing said compound, along with an active ingredient, which can be administered safely to humans. The present invention further relates to a method for preserving an emulsion, which comprises adding a sorbic acid or a pharmaceutically acceptable salt thereof to said emulsion. The present invention moreover relates to use of sorbic acid or a pharmaceutically acceptable salt thereof for the preservation of an emulsion, as well as to use of said compound for the production of an emulsion and a preservative for emulsion.
When formulating a drug into an eye drop, a nasal drop or an ear drop, a preservative is added to eliminate a secondary contamination with microorganisms present in the air, lacrimal fluid, meatus nasi, external auditory meatus and the like. The same applies to an emulsion. Thus, paraoxybenzoate, benzalkonium chloride and the like are generally added as a preservative when formulating a drug into an emulsion. However, such conventional preservatives cannot provide an emulsion, particularly an oil in water type (o/w type) emulsion, with a sufficient preservation effect. In addition, when a dispersion medium has a relatively high pH, microorganisms tend to proliferate, further reducing the preservation effect. Nevertheless, an increased amount of a preservative for a higher preservation effect is associated with possible side effects such as greater irritation etc. to the living body due to the high concentration preservative.
Thus, there is a dilemma as to whether to add a preservative at a high concentration to increase preservation effect or limit the amount to be added to avoid side effects caused by the high concentration preservative, when formulating a drug into an emulsion. Therefore, development of a preservative capable of imparting a superior preservation capability to an emulsion at a low concentration has been demanded.
It is therefore an object of the present invention to provide a compound capable of imparting a superior preservation capability to an emulsion even when added at a low concentration, particularly an oil in water type (o/w type) emulsion, among others, an oil in water type emulsion comprising a dispersion medium having a high pH, and a preservative for emulsion containing said compound.
Another object of the present invention is to provide an emulsion containing said compound or said preservative, which has superior preservation effect and which can be administered safely to humans, particularly an emulsion for an eye drop, a nasal drop and an ear drop.
As a result of intensive studies in an attempt to solve the above-mentioned problems, it has now been found that the addition of sorbic acid or a pharmaceutically acceptable salt thereof to an emulsion leads to a high preservation effect of the emulsion, even when the concentration thereof is low. It has also been found that, when the emulsion has a high pH, the addition, at a low concentration, of sodium edetate and boric acid along with the sorbic acid or a pharmaceutically acceptable salt thereof also leads to a more superior preservation effect of the emulsion.
In one aspect, the present invention provides a preservative for emulsion which contains sorbic acid or a pharmaceutically acceptable salt thereof, particularly such preservative for emulsion which contains said compound at a concentration of 0.001-5 w/v %, preferably 0.01-1 w/v %; further, the above-mentioned preservative for emulsion which contains, in addition to said compound, sodium edetate and boric acid, particularly said preservative for emulsion which contains sodium edetate at a concentration of 0.001-0.2 w/v %, preferably 0.005-0.1 w/v %, and boric acid at a concentration of 0.001-10 w/v %, preferably 0.01-5 w/v %; and further, the above-mentioned preservative for emulsion which is in the dosage form of an eye drop, a nasal drop or an ear drop.
In another aspect, the present invention provides an emulsion which contains sorbic acid or a pharmaceutically acceptable salt thereof, or a preservative for emulsion containing said compound, together with an active ingredient and a pharmaceutically acceptable carrier, particularly, the above-mentioned emulsion containing sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, particularly 0.01-1 w/v %; further, an emulsion comprising a preservative containing sorbic acid or a pharmaceutically acceptable salt thereof, sodium edetate and boric acid, together with an active ingredient and a pharmaceutically acceptable carrier, or an emulsion comprising a preservative containing sorbic acid or a pharmaceutically acceptable salt thereof, sodium edetate and boric acid, together with an active ingredient and a pharmaceutically acceptable carrier; particularly, the above-mentioned emulsion containing sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, preferably 0.01-1 w/v %, sodium edetate at a concentration of 0.001-0.2 w/v %, preferably 0.005-0.1 w/v %, and boric acid at a concentration of 0.001-10 w/v %, particularly 0.01-5 w/v %; and further, the above-mentioned emulsion which is in the dosage form of an eye drop, a nasal drop or an ear drop.
In another aspect, the present invention provides a commercial package containing a preservative for emulsion containing sorbic acid or a pharmaceutically acceptable salt thereof, and, where necessary, sodium edetate and boric acid, along with a pharmaceutically acceptable carrier, and a package insert stating that said preservative is useful for the preservation of the emulsion; and a commercial package comprising either an emulsion containing sorbic acid or a pharmaceutically acceptable salt thereof, and, where necessary, sodium edetate and boric acid, together with an active ingredient and a pharmaceutically acceptable carrier, or a preservative for emulsion containing sorbic acid or a pharmaceutically acceptable salt thereof, and, where necessary, sodium edetate and boric acid, together with an active ingredient and a pharmaceutically acceptable carrier, and a package insert stating that sorbic acid, a pharmaceutically acceptable salt thereof and the combination of said compound, sodium edetate and boric acid are useful for the preservation of an emulsion.
Also, the present invention provides a preservation method of an emulsion, which comprises adding sorbic acid or a pharmaceutically acceptable salt thereof to an emulsion at a concentration pharmaceutically acceptable and effective for the preservation of the emulsion, particularly, sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, preferably 0.01-1 w/v %. The present invention further provides a preservation method of an emulsion, which comprises adding sorbic acid or a pharmaceutically acceptable salt thereof, sodium edetate and boric acid to an emulsion at concentrations pharmaceutically acceptable and effective for the preservation of the emulsion, particularly, sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, preferably 0.01-1 w/v %, sodium edetate at a concentration of 0.001-0.2 w/v %, preferably 0.005-0.1 w/v %, and boric acid at a concentration of 0.001-10 w/v %, preferably, 0.01-5 w/v %. The present invention is a preservation method of the above-mentioned emulsion in the dosage form of an eye drop, a nasal drop or an ear drop.
The present invention also provides use of sorbic acid or a pharmaceutically acceptable salt thereof for the preservation of an emulsion, particularly, use comprising adding sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, particularly 0.01-1 w/v %. Further, the present invention provides the use of sorbic acid or a pharmaceutically acceptable salt thereof, sodium edetate and boric acid for the preservation of an emulsion, particularly, the use comprising adding sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, particularly 0.01-1 w/v %, sodium edetate at a concentration of 0.001-0.2 w/v %, particularly 0.005-0.1 w/v %, and boric acid at a concentration of 0.001-10 w/v %, particularly 0.01-5 w/v %. The present invention provides use wherein said emulsion is in the dosage form of an eye drop, a nasal drop or an ear drop.
In a further aspect, the present invention provides use for the production of an emulsion or a preservative for an emulsion, which comprises adding sorbic acid or a pharmaceutically acceptable salt thereof, particularly sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, preferably 0.01-1 w/v %. Further, the present invention provides the above-mentioned use for the production of an emulsion or a preservative for emulsion, which comprises adding sorbic acid or a pharmaceutically acceptable salt thereof, sodium edetate and boric acid, particularly sorbic acid or a pharmaceutically acceptable salt thereof at a concentration of 0.001-5 w/v %, preferably 0.01-1 w/v %, sodium edetate at a concentration of 0.001-0.2 w/v %, preferably 0.005-0.1 w/v %, and boric acid at a concentration of 0.001-10 w/v %, preferably 0.01-5 w/v %. The present invention provides the above-mentioned use wherein said emulsion is in the dosage form of an eye drop, a nasal drop or an ear drop.
The inventive preservative for emulsion contains sorbic acid or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the sorbic acid to be used in the present invention is exemplified by alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and the like.
When the preservative for emulsion of the present invention is added to an emulsion having a pH of not less than 6.0, it is preferable that said preservative for emulsion contain sodium edetate and boric acid, in addition to sorbic acid or a pharmaceutically acceptable salt thereof.
The concentration of sorbic acid or a pharmaceutically acceptable salt thereof to be contained in the preservative for emulsion is 0.001-5 w/v %, preferably 0.01-1 w/v %. When sodium edetate and boric acid are further contained, the concentration of sodium edetate is 0.001-0.2 w/v %, preferably 0.005-0.1 w/v %, and that of boric acid is 0.001-10 w/v %, preferably 0.01-5 w/v %.
The inventive preservative for emulsion may contain, besides sorbic acid or a pharmaceutically acceptable salt thereof, emulsifiers such as polysorbate 80 and polyoxyethylene hydrogenated castor oil 60, buffering agents such as sodium acetate and disodium hydrogenphosphate, isotonizing agents such as sodium chloride and glycerin, and the like.
The inventive preservative for emulsion can be prepared by a known method. For example, sorbic acid or a pharmaceutically acceptable salt thereof is dissolved in sterile purified water or an aqueous solvent. In this solution is dissolved, as necessary, sodium edetate and boric acid, and the above-mentioned additives are added on demand.
The inventive preservative for emulsion is not subject to any particular limitation as long as it can be added to any emulsion. When it is used for an oil in water (o/w) type emulsion, said preservative becomes a dispersion medium, and when it is used for a water in oil (w/o) type emulsion, said preservative becomes a disperse phase.
The inventive preservative for emulsion can achieve superior preservation effect in various types of emulsions such as oil in water (o/w) type emulsion, even when added at a low concentration. By adding the inventive preservative for emulsion to an emulsion, therefore, the emulsion shows high preservation effect and extremely less side effects, as a result of the low concentration of the preservative.
The emulsion of the present invention is not particularly limited as to use thereof as long as it contains sorbic acid or a pharmaceutically acceptable salt thereof, or the above-mentioned preservative for emulsion, together with the active ingredient. For example, it is a therapeutically useful emulsion. The drug to be the active ingredient is not particularly limited, and is exemplified by various drugs such as steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agent, antibiotics, anti-viral agent, lipid-soluble vitamin and the like, and combinations thereof.
The concentration of sorbic acid or a pharmaceutically acceptable salt thereof in the inventive emulsion is 0.001-5 w/v %, preferably 0.01-1 w/v %. When sodium edetate and boric acid are additionally contained, the concentration of sodium edetate is 0.001-0.2 w/v %, preferably 0.005-0.1 w/v %, and that of boric acid is 0.001-10 w/v %, preferably 0.01-5 w/v %.
While the content of the active ingredient of the inventive emulsion varies depending on the kind of drug to be contained, when the inventive emulsion contains a steroidal anti-inflammatory agent as the active ingredient, the concentration thereof is about 0.001-5 w/v %, preferably about 0.005-1 w/v %, and more preferably about 0.01-0.5 w/v %.
The oil to be contained in the inventive emulsion is preferably low toxic and less stimulating, particularly applicable to the eye, nose, ear and the like. Examples thereof include castor oil, peanut oil, cotton seed oil, soybean oil, olive oil, medium chain fatty acid triglyceride, oleic acid and the like.
The emulsion of the present invention may contain a non-ionic surfactant as an emulsifier to increase stability during emulsification. Examples of the non-ionic surfactant include polyoxyethylene sorbitan fatty acid ester (e.g. polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and the like), polyoxyethylene hydrogenated castor oil 60, sorbitan fatty acid ester (e.g. sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and the like), polyoxyethylene alkyl ether (e.g. polyoxyethylene lauryl ether and the like), polyoxyethylene fatty acid ester (e.g. polyoxyethylene monostearate and the like), and the like.
A buffering agent can be added to the emulsion of the present invention. Examples of the buffering agent include acetate such as sodium acetate, phosphate such as sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium dihydrogenphosphate and dipotassium hydrogenphosphate, amino acid salt such as xcex5-aminocaproic acid and sodium glutamate, boric acid and a salt thereof, citric acid and a salt thereof, and the like.
The emulsion of the present invention may contain an isotonizing agent. Examples of the isotonizing agent include sodium chloride, glycerin, glucose, mannitol, sorbitol and the like.
The emulsion of the present invention may also contain various additives such as stabilizer, antioxidant, chelating agent, pH adjusting agent, thickener and the like. Examples of the antioxidant include ascorbic acid and salt thereof, tocopherol, sodium thiosulfate, sodium bisulfite, pyrvic acid and salt thereof, and the like. Examples of the chelating agent include sodium edetate, citric acid and salt thereof, and the like. The pH adjusting agent is exemplified by hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, aqueous ammonia, and the like. The pH of the inventive emulsion is preferably 2.5-8.5.
The dispersed particles of the emulsion of the present invention preferably have a median diameter of 5-0.0001 xcexcm, more preferably 1-0.001 xcexcm.
The emulsion of the present invention can be prepared by a known method. To be specific, sorbic acid or a pharmaceutically acceptable salt thereof, and, where necessary, sodium edetate and boric acid, and the active ingredient are dissolved in water or an aqueous solvent, if the active ingredient is water soluble. An oily phase is prepared separately (when the active ingredient is lipid-soluble, it is dissolved in this oily phase), and emulsified with the aqueous phase prepared above. As the case demands, an emulsifier and other additives can be added to the aqueous phase and/or oily phase.
More specifically, in the case of an oil in water type emulsion, for example, sorbic acid or a pharmaceutically acceptable salt thereof and, where necessary, sodium edetate and boric acid, and further, the above-mentioned additive and emulsifier are dissolved in water, and the pH thereof is adjusted to 2.5-8.5 with a pH adjusting agent. For homogeneous emulsification, a known means such as a mixer, homogenizer, microfluidizer, high pressure homogenizer and the like can be used.
Alternatively, the inventive emulsion can be prepared by the following method. That is, emulsifier and other additive are added as necessary to the inventive preservative for emulsion prepared in advance, which may comprise sorbic acid or a pharmaceutically acceptable salt thereof and, where necessary, sodium edetate and boric acid. When the active ingredient is water soluble, it is dissolved in said mixture to give an aqueous phase. Separately, emulsifier and other additive are added as necessary to an oil, and when the active ingredient is lipid soluble, it is dissolved in said oil to give an oily phase. Then, said aqueous phase and oily phase are emulsified by a known method.
The emulsion of the present invention is preferably used as an emulsion for local administration to the eye, nose or ear. More preferably, it is formulated into a dosage form for instillation to the eye, nose or ear.
The emulsion of the present invention shows high preservation property attributable to the preservative contained therein, which is capable of exerting superior preservation effect even at a low concentration, and thus, is associated with extremely less side effects caused by the preservative.
The present invention is described in more detail by way of Examples and Experimental Examples, which should not be construed as limiting the invention.